The present invention relates to a membrane and a chamber of a drug delivery device which is for delivery of a drug comprising a mixture of first and second substances and which includes the chamber for housing the first substance, another chamber for housing the second substance and the membrane for partitioning the first chamber from the second chamber to prevent mixture of the first and second substances until the device is activated. The invention further relates to a drug delivery device of the aforementioned type, one example of which being an automatic injector.
There are certain instances when a person will need to inject a drug solution at a time which cannot be predicted, for example soldiers in the field who have been subject to a nerve gas attack. It is therefore important that such a person be provided with an injector which can be handled and activated in a simple and quick manner and which is reliable. Automatic injectors have therefore been developed in response to this need.
Automatic injectors will invariably be stored for many years prior to use and preferably such storage should be able to be at elevated temperatures up to 40xc2x0 C., that is to say, there should be no need for cold storage under normal conditions (normal ambient temperatures, body temperatures). Automatic injectors will also often be subjected to hard conditions during the period when potential users carry them. The shelf-life of automatic injectors is therefore equally important With this in mind, the stability of drug solutions may deteriorate when stored for long periods. This is the case for certain nerve gas antidotes which are stable in powder form but which prove difficult to stabilise in solution for long storage periods.
There is thus a demand for an automatic injector for delivery of a drug solution which is simple, quick and reliable, in which it is possible to store the components which when mixed form the drug solution separately for a long period and in which means are provided which on activation of the injector causes the components to be mixed easily for injection of the drug solution.
An automatic injector which meets this requirement is made known in EP-A-288443.
EP-A-288443 makes known an automatic injector for delivery of a drug solution comprising a mixture of first and second substances, the device having a first chamber which contains the first substance, a second chamber which contains the second substance and a membrane which on activation of the injector moves from a first disposition in which it partitions the first and second chambers to prevent mixture of the first and second substances to a second disposition in which it enables the first and second substances to be mixed for injection thereof.
It will be apparent that the construction of the membrane needs to be such as to prevent premature mixing of the first and second substances. The membrane must therefore present a barrier against migration of the first and second substances therethrough. The membrane should also (i) be relatively easy to manufacture, (ii) not absorb substances from the substances in the chambers nor emit substances to those substances, and (iii) meet high standards in regard of gas permeability and radiation, e.g. should be able to withstand the normal radiations used for sterilisation, for example gamma and lambda radiation.
The automatic injector of EP-A-288443 is described with reference to its use for delivery of a drug solution formed on mixing of a powder with a liquid, as needed for the nerve gas antidotes of the type mentioned hereinabove which are stable in powder form but not stable for long periods when in solution. One of the chambers of the injector thus houses the powder (hereinafter the xe2x80x9cpowder chamberxe2x80x9d) while the other chamber houses a liquid for the powder to be mixed with (hereinafter the xe2x80x9cliquid chamberxe2x80x9d). As mentioned above, it should be possible to store the injector for long periods and preferably at an elevated temperature. This means that the long-term and short-term requirements regarding the impermeability of the membrane to the liquid and liquid vapour has to be very strict.
In most cases the liquid for mixing with the powder will be water-based. With this in mind, it is previously known to use a membrane which contains aluminium as a barrier material to water and water vapour, as for example in the automatic injector of EP-A-288443.
In certain instances it may be that the pH of the substances in the chambers needs adjusting for stabilising purposes, this being particularly so for storage at elevated temperatures. This can have an adverse effect on the long-term integrity of the membrane. Furthermore, one of the substances may be chemically aggressive per se with respect to the material/materials of the membrane and thus also have an impact on the long-term integrity of the membrane, a condition being aggravated at elevated temperatures.
This is the case where the automatic injector of EP-A-288443 is to deliver a nerve gas antidote with the powder chamber of the injector containing HI-6 powder and the liquid chamber housing a mixture of Atropine and Avizaphone. In this instance, the pH of the Avizaphone/Atropine mixture is adjusted to a low pH value of pH 4 to increase the stability of the Atropine. This low pH value, however, has a deleterious effect over time on the aluminium contained in the membrane. Moreover, Avizaphone is chemically aggressive with respect to aluminium. The shelf-life of the automatic injector is thus handicapped by the poor resistance of the aluminium barrier material to the properties of the Atropine/Avizaphone liquid mixture.
There is thus a need for a membrane separating the liquid and powder chambers in this automatic injector which has improved resistance against the liquid mixture in addition to presenting a barrier against liquid or liquid vapour permeating into the powder chamber from the liquid chamber and adversely affecting the powder, for example by causing the powder to recrystallise and hence decrease the solubility of the powder or otherwise deteriorate the powder.
In the automatic injector of EP-A-288443 the membrane in its first disposition is welded across the powder chamber to close off the powder chamber and separate the contents of the powder chamber from the contents of the liquid chamber. A piston then acts on the powder in the powder chamber on activation of the injector to build up sufficient hydraulic pressure to bring the membrane to the second disposition by rupture thereof A recent development to the injector, though, has seen the piston being provided with a leading edge which on activation of the injector causes the membrane to be brought to the second disposition by peeling of the membrane off the powder chamber This has the advantage that the membrane can be made stronger. On the other hand, though, this places certain requirements on the weld formed between the membrane and the powder chamber.
With this in mind, it has been previously proposed to form the powder chamber from polypropylene with the membrane having a laminate construction comprising a layer of aluminium on one of the major surfaces of which a layer of welding material is adhered for welding the membrane to the powder chamber. The use of polypropylene to form the powder chamber, however, gives rise to difficulties in finding a material suitable for welding the membrane to the powder chamber. The welding materials either form a weld joint which is too weak thereby compromising the shelf-life of the injector or a weld joint that is too strong thereby compromising the ability of the membrane to be easily displaced to the second disposition on activation of the injector by peeling off.
There is thus also the need for a powder chamber which presents a surface to which it is easier to weld the membrane.
The present invention therefore proposes to satisfy these needs. It is to be pointed out, however, that the invention has application to the general field of devices which are for delivering a drug comprising a mixture of substances and which are provided with chambers for separately housing the substances until such time as the device needs to be used whereupon the substances are mixed for delivery of the drug by the device, that is to say, the invention is not restricted to the case of automatic injectors of the type hereinabove described.
According to a first aspect of the present invention there is provided a membrane for partitioning first and second chambers in a drug delivery device for delivery of a drug comprising a mixture of first and second substances, the first and second chambers respectively being for housing the first and second substances, characterised in that the membrane comprises a barrier material comprising polychlorotrifluoroethylene or a copolymer thereof, polyvinylidene chloride or a copolymer thereof or a silicon oxide. These barrier materials have a greater resistance to the corrosive environments that afflict the previously proposed barrier material of aluminium.
According to a second aspect of the present invention there is provided a drug delivery device for delivery of a drug which comprises a mixture of a first substance and a second substance, the device including a first chamber for housing the first substance, a second chamber for housing the second substance and a membrane which on application of a predetermined condition thereto is movable from a first disposition in which it partitions the first and second chambers to prevent mixture of the first and second substances to a second disposition in which it enables the first and second substances to be mixed characterised in that the membrane comprises a barrier material comprising polychlorotrifluoroethylene or a copolymer thereof, polyvinylidene chloride or a copolymer thereof or a silicon oxide.
The term xe2x80x9cdrug delivery devicexe2x80x9d is to be taken as covering not only a complete device but also a cartridge, ampoule or the like which includes the partitioned first and second chambers and which is separable from the complete device.
It will be appreciated that the drug delivery device of the invention may be for delivery of a drug which is formed from more than just a mixture of first and second substances. In this case, the drug delivery device of the invention may include further chambers for separately housing the additional substances which together with the first and second substances will form the drug.
In an embodiment of the invention hereinafter to be described the membrane is a laminate structure composed of a plurality of layers and the barrier material is contained in at least one layer of the laminate structure.
In an embodiment of the invention hereinafter to be described the laminate structure includes an outer layer of a material which enables the laminate structure to be welded to the first chamber to close the first chamber off and thereby partition the first and second chambers. Preferably, the outer layer is formed of a material which when welded to the first chamber results in a weld joint which enables the membrane to be brought to its second disposition by peeling of the membrane off the first chamber. Amongst other things, this allows the strength of the membrane to be greater than in the case where the membrane is to be brought to the second disposition by rupture thereof.
In an embodiment of the invention the outer layer is formed from a polyethylene or cellulose based polymer and the first chamber is formed of polypropylene or a copolymer thereof or of a polyethylene based polymer. Where polyethylene based polymers form the outer welding layer and the first chamber there may be mentioned blends of polyethylene with ethylene-vinyl acetate (EVA), ethylene-butyl-acrylate (EBA), polybutylene (PB) or butyl acrylate (BA), cross-linked polyethylenes and polyethylene ionomers as the material for the outer welding layer and polyethylene or high density polyethylene for the material of the first chamber. Alternatively, the outer layer can be formed of polypropylene, for instance a polypropylene lacquer, or a blend of polypropylene and butyl acrylate and the first chamber is of polypropylene or a copolymer thereof.
In an embodiment of the invention hereinafter to be described the barrier material is contained in a barrier layer of the laminate structure and the laminate structure includes a layer of a polyester material, for example polyethylene terephthalate, which is mounted to one of the major surfaces of the barrier layer such that the polyester layer spaces the barrier layer from the outer layer.
For ease of manufacture of the membrane and mounting thereof in certain drug delivery devices the polyester layer is a first polyester layer and the laminate structure further includes a second layer of a polyester material, for example of polyethylene terephthalate, which is mounted to the major surface of the barrier layer opposite to that on which the first polyester layer is mounted.
Where the barrier material is silicon oxide it may be useful for the silicon oxide to be supported in a matrix material, for example in a matrix of polyethylene terephthalate, as is sold by Mitsubishi under the brand name Techbarrier-S. The silicon oxide may be silicon dioxide.
According to a third aspect of the present invention there is provided the use of polychlorotrifluoroethylene or a copolymer thereof, polyvinylidene chloride or a copolymer thereof or a silicon oxide in the manufacture of a membrane for positioning in a drug delivery device for delivery of a drug comprising a mixture of first and second substances such that the membrane partitions a pair of chambers in the device which respectively house the first and second substances until the device is activated.
According to a fourth aspect of the present invention there is provided a drug delivery device for delivery of a drug comprising a mixture of first and second substances, the device having a first chamber for housing the first substance, a second chamber for housing the second substance and a membrane which on application of a predetermined condition thereto is movable from a first disposition in which it partitions the first and second chambers to prevent mixture of the first and second substances to a second disposition in which it enables the first and second substances to be mixed, wherein in the first disposition an outer surface of the membrane is welded to a surface of the first chamber characterised in that at least the surface of the first chamber to which the outer surface of the membrane is welded is presented by a polyethylene based polymer. The use of a polyethylene based polymer for forming the welding surface of the first chamber provides greater variety of welding materials that can be used to present the outer surface of the membrane and which form a satisfactory weld joint with the first chamber, i.e. not too strong and not too weak. As examples, polyethylene or cellulose based polymers may be used to present the outer surface of the membrane.
According to a fifth aspect of the present invention there is provided a chamber for a drug delivery device which is for delivery of a drug comprising a mixture of first and second substances and which in an assembled non-activated state will include the chamber as a first chamber for housing the first substance, a second chamber for housing the second substance and a membrane welded across the first chamber to partition the first chamber from the second chamber and thereby prevent mixture of the first and second substances until the device is activated characterised in that the surface of the first chamber to which the membrane is welded in the assembled non-activated state of the device is presented by a polyethylene based polymer.
According to a sixth aspect of the present invention there is provided the use of a polyethylene based polymer in the manufacture of a first chamber of a drug delivery device which is for delivery of a drug comprising a mixture of first and second substances and which includes the first chamber for housing the first substance, a second chamber for housing the second substance and a membrane movable on application of a predetermined condition thereto from a first disposition in which it is welded across the first chamber to partition the first chamber from the second chamber and thereby prevent mixture of the first and second substances to a second disposition in which it enables the first and second substances to be mixed for delivery of the drug by the device.
In an embodiment of the invention according to its fourth, fifth and sixth aspects the polyethylene based polymer is polyethylene or high density polyethylene.